Chemotaxis factors
The directed migration of immune cells begins with the recognition of specific substances called chemoattractants. They can be broadly divided into external and internal.
- Bacterial peptides. Contain N-formylmethionine, which initiates protein synthesis in bacteria. Eukaryotes lack it, so for the immune system it acts as a clear danger signal (PAMP). Neutrophils, monocytes, and macrophages respond to it.
- Endogenous pro-inflammatory factors. Formed directly at the site of inflammation. These include anaphylatoxins (small complement fragments C3a and C5a), leukotrienes (lipid derivatives of arachidonic acid), neuropeptides, fibrin degradation products, and pentraxins (e.g., C-reactive protein).
- Chemokines (Chemotactic cytokines). This is a family of cytokines specialized in cell recruitment. They are produced by activated myeloid and endothelial cells directly at the site of inflammation (classic examples include the pro-inflammatory cytokine IL-1β or specific chemokines such as interleukin-8).
Reception and signal regulation
To capture chemotactic factors, cells use receptors of the rhodopsin-like family (e.g., FPR and FPLR). These molecules cross the cell membrane seven times and work in close coordination with G proteins.
Binding of the ligand to the receptor activates the G protein, triggering intracellular GDP exchange. This leads to cytoskeletal rearrangement and migration.
Importantly, the system features a self-limiting (desensitization) mechanism. The α-subunit of the G protein possesses weak GTPase activity. During operation, it hydrolyzes GTP to GDP. Afterward, the α-subunit reassociates with the βγ dimer into an inactive trimer. The complex rebinds to the chemokine receptor, and intracellular signal transduction stops.
Mechanism of cell movement (polarization)
For a cell to move, strict coordination of intracellular processes must occur within it. The cell morphologically and functionally divides into several zones:
- Leading edge (pseudopodia / lamellipodia). Here, receptors detect the chemical gradient. Signals from G proteins activate phosphoinositide 3-kinase (PI3K) with the formation of PIP3, as well as small GTPases (Cdc42, Rac). The main effect is F-actin polymerization, causing the cell to extend a forward protrusion.
- Cell adhesion zone. The signal is transmitted via phospholipase C (PLC) and diacylglycerol (DAG) to the RAPL molecule. This leads to the activation of integrins, which ensure firm attachment of the cell to the substrate or vessel wall.
- Trailing edge (uropod). The small GTPase Rho and associated kinase ROCK stimulate the formation of actomyosin complexes. Their contraction causes retraction of the trailing edge, completing a step of cell movement.
Thus, the movement cycle includes: increased adhesion $\rightarrow$ polarization $\rightarrow$ polymer actin assembly $\rightarrow$ lamellipodia protrusion $\rightarrow$ actomyosin contraction.
Briefly: answers to topical questions
What classes of chemokines are distinguished based on the arrangement of cysteine residues?
Depending on the relative arrangement of cysteine residues, four groups of chemokines are distinguished.
- α-Chemokines (CXC chemokines) — cysteine residues are separated by any single amino acid residue.
- β-Chemokines (CC chemokines) — cysteine residues follow each other directly.
- γ-Chemokines (C chemokines) — have only two cysteine residues, one of which is located near the N-terminus.
- δ-Chemokines (CX3C chemokines) — N-terminal cysteine residues are separated by any three amino acids.
Which receptors specifically bind CC and CXC family chemokines?
CC and CXC family chemokines specifically bind to corresponding rhodopsin-like receptors designated by the abbreviations CCR and CXCR.
| Chemokine family | Specific receptors |
|---|---|
| CXC chemokines | CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 |
| CC chemokines | CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 |
At the same time, a single receptor can interact with multiple chemokines, and a single chemokine can be recognized by different receptors. For example, pro-inflammatory CXC chemokines 1–8 interact with CXCR1 and CXCR2, while ligands of the MIG, IP-10, and ITAC subgroup bind to CXCR3.
What mechanisms and mediators suppress and stop leukocyte chemotaxis?
Suppression and cessation of leukocyte chemotaxis are ensured by receptor desensitization mechanisms and enzymatic inactivation of chemokines.
- Receptor desensitization (self-limitation) — the Gα subunit hydrolyzes GTP to GDP, after which it reassociates with the Gβγ dimer. The resulting inactive trimer restores its bond with the chemokine receptor, terminating intracellular signal transmission.
- Enzymatic inhibition (by metalloproteinases) — the individual N-terminal part of a chemokine can be cleaved by metalloproteinases. As a result, the modified molecule acquires inhibitory properties.
How to remember the zones of a moving cell: PAR — Pseudopodia/Leading edge (Actin polymerization), Adhesion (Integrin activation), Retraction of the uropod (actomyosin function).
Class and exam questions
Why do bacterial peptides attract immune cells?
They contain N-formylmethionine, which is essential for bacterial protein synthesis but completely absent in eukaryotes. For leukocytes, this is an infallible marker of a foreign agent.
How is signal termination achieved in a chemokine receptor?
The G protein cleaves GTP to GDP due to its intrinsic enzymatic activity. After that, its subunits assemble into an inactive complex, blocking the receptor.
How does the trailing edge of the cell pull forward during movement?
Due to the action of the small GTPase Rho and the kinase ROCK, which trigger the formation and contraction of actomyosin complexes in the uropod.
What else to study on this topic
- Modeling chemotaxis in vitro using a synthetic fMLP analog.
- The role of anaphylatoxins (C3a, C5a) in the development of systemic inflammatory responses.
- Arachidonic acid metabolism and the functions of leukotrienes in allergy.
- Diversity of leukocyte rhodopsin-like receptors.
- Small GTPase cascades (Cdc42, Rac, Rho) and their cytoskeletal targets.
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